Ophn1 gene encodes Oligophrenin-1 (OPHN1), a Rho-GAP protein highly expressed in neurons. In humans, all Ophn1 mutations cause the loss of function of OPHN1 leading to syndromic intellectual disability (ID). In neurons, OPHN1 regulates dendritic spine density and architecture, actin dynamics and AMPA receptor (AMPAR) trafficking. Interestingly, we identified for the first time OPHN1 as a novel target of sumoylation. Sumoylation is a post-translational modification essential to the modulation of several neuronal functions, including neurotransmitter release and synaptic plasticity. Altered sumoylation has been associated with neurological disorders. Here, we combined molecular biology with live imaging and super resolution microscopy to address the role of sumoylation in controlling OPHN1 function in hippocampal neurons. Excitingly, we demonstrated that sumoylation controls the activation state of OPHN1 by promoting a conformational change that induces the release of the autoinhibitory interaction between the BAR and the GAP domain of OPHN1. By this mechanism, sumoylation tunes the actin dynamics, which in turn impacts dendritic spine density and architecture. Furthermore, we demonstrated that a novel ID-related missense mutation compromises OPHN1 sumoylation by altering the proper conformation of the protein and impairing its physiological regulation. This rises thrilling hypothesis that compromised sumoylation participates to synaptic dysfunctions associated to the ID phenotype by altering the autoinhibitory mechanism that controls OPHN1 function.